Metastatic Cutaneous Basal Cell Carcinoma: Report of 2 Cases Preceding the Hedgehog Pathway Antagonists Era.

Basal cell carcinoma (BCC) of the skin is the most common type of malignant human tumor. However, metastatic BCC is a very rare event with weakly effective therapeutic options and a poor prognosis, until a few years ago. In 2012, small-molecule therapies, capable of inactivating the hedgehog signaling pathway and thus reducing tumor growth and progression, were introduced into clinical practice for the treatment of patients with advanced BCC. We present retrospectively 2 personal cases of metastatic BCC of the skin, from the premolecular therapy era, from primary tumors that arose years before in the head and neck area. The former case occurred in a 45-year-old woman with a history of recurrent BCC of the retroauricular skin who eventually died due to diffuse metastatic spread. The latter case concerned a 70-year-old man also with a history of recurrent BCC of the nasal-perinasal skin who developed multiple subcutaneous and lymph node metastases in the neck. In both cases, the diagnoses were based on biopsies of the metastatic sites. The first patient died 5 months after the diagnosis of metastatic disease, while the second was alive and disease-free 2 years after neck lymph node dissection and external radiation therapy, and then lost to follow-up. We extensively discuss several tumor entities with basal or basaloid features that may enter the differential diagnosis with BCC in metastatic sites. In addition, we briefly summarize the advances in clinical therapeutics using small molecules, which are now an integral part of the treatment of such advanced BCC cases.

Metastatic Basal Cell Carcinoma of the Skin: A Comprehensive Literature Review, Including Advances in Molecular Therapeutics.

Basal cell carcinoma (BCC) of the skin is the most common type of malignant human tumor. In Europe, the incidence of BCC ranges from 44.6 to 128 cases per 100,000 inhabitants annually, whereas in the United States, the yearly incidence rate ranges between 500 and 1500. The global incidence has been calculated to be as high as 10 million cases of BCC per year. There are 2 main clinical patterns of BCC-the familial BCC in basal cell nevus syndrome and sporadic BCC. The etiology of cutaneous BCC is usually the result of the interaction between solar ultraviolet radiation and genetic factors. Somatic or germline mutations in the effector components of the hedgehog signaling pathway (ie, PTCH1, PTCH2, SMO or SUFU genes) are responsible for ∼90% of the cases of both sporadic and familial BCC, all causing a constitutive activation of the hedgehog pathway. Cutaneous BCC very rarely metastasizes, and diagnosis in metastatic sites can be very difficult. Metastatic BCC has weakly effective therapeutic options with a poor prognosis until few years ago. In 2012, small-molecule therapies, involving inactivation of the hedgehog signaling pathway, and capable of reducing tumor growth and progression have been introduced into clinical practice for advanced (locally advanced or metastatic) BCC. We performed a comprehensive literature review on metastatic BCC and found at least 915 cases reported to date. In addition, we extensively discussed the differential diagnosis of metastatic BCC, and outlined the advances in clinical therapeutics involving these small molecules.

Anaplastic Kaposi's Sarcoma of the Adrenal in an HIV-negative Patient With Literature Review.

Kaposi's sarcoma (KS) is a peculiar tumor of viral etiology, with the HHV8 rhadinovirus playing a fundamental role in its development. Several epidemiological categories of KS have been identified, of which the sporadic, endemic, iatrogenic, and the epidemic are the main ones. Several histologic disease morphologies have been described, such as inflammatory, angiomatous, spindle cell, mixed, and the anaplastic (sarcomatous) subtypes. The skin of the limbs is most commonly affected, but any other organ or site may be involved. Microscopically KS may enter the differential diagnosis with several different entities, and for this purpose the immunohistochemical detection of the viral latent nuclear antigen-1 (LNA-1) may be crucial. Sporadic KS is usually benign, but rarely it may be aggressive. Anaplastic histology heralds an ominous course in any clinical context. We report a case of anaplastic retroperitoneal KS, occurring in an HIV-negative adult man. This patient presented with a huge left suprarenal mass, which was totally resected, and initially diagnosed as inflammatory leiomyosarcoma, because of the monomorphic spindle cell tumor morphology. After 12 years the tumor recurred locally as an unresectable mass, which was biopsied and examined. At the time of recurrence, the histologic slides of the primary tumor were reviewed, and the previous diagnosis was changed to that of atypical KS. Histologically the recurrent tumor showed both spindle cell and epithelioid appearances. Strongly diffuse HHV8/LAN-1 immunopositivity was documented in both tumors. The final diagnosis for the entire case was anaplastic KS. Then, the patient died in a few months.

Extraneuraxial Hemangioblastoma: Clinicopathologic Features and Review of the Literature.

Extraneuraxial hemangioblastoma occurs in nervous paraneuraxial structures, somatic tissues, and visceral organs, as part of von Hippel-Lindau disease (VHLD) or in sporadic cases. The VHL gene plausibly plays a key role in the initiation and tumorigenesis of both central nervous system and extraneuraxial hemangioblastoma, therefore, the underlying molecular and genetic mechanisms of the tumor growth are initially reviewed. The clinical criteria for the diagnosis of VHLD are summarized, with emphasis on the distinction of sporadic hemangioblastoma from the form fruste of VHLD (eg, hemangioblastoma-only VHLD). The world literature on the topic of extraneuraxial hemangioblastomas has been comprehensively reviewed with ∼200 cases reported to date: up to 140 paraneuraxial, mostly of proximal spinal nerve roots, and 65 peripheral, 15 of soft tissue, 6 peripheral nerve, 5 bone, and 39 of internal viscera, including 26 renal and 13 nonrenal. A handful of possible yet uncertain cases from older literature are not included in this review. The clinicopathologic features of extraneuraxial hemangioblastoma are selectively presented by anatomic site of origin, and the differential diagnosis is emphasized in these subsets. Reference is made also to 10 of the authors' personal cases of extraneuraxial hemangioblastomas, which include 4 paraneuraxial and 6 peripheral (2 soft tissue hemangioblastoma and 4 renal).

Lipophyllodes of the breast. A reappraisal of fat-rich tumors of the breast based on 22 cases integrated by immunohistochemical study, molecular pathology insights, and clinical follow-up.

We have studied 22 cases of mammary lipophyllodes tumors (LPT), analyzing their clinicopathologic features along with available follow-up. All cases were tested for cytokeratins, S100 protein, and MDM2, and in selected cases for estrogen receptor, smooth muscle actin, bcl2, desmin, and myogenin. Patients were women aged 21 to 69 years (average, 45 years), and LPT size ranged from 1.6 to 30 cm (average, 9.7 cm). Microscopically, LPT segregated as follows: atypical lipoma-like tumor/well-differentiated liposarcoma (ALT/WDL), 8 cases; myxoid, 6; and pleomorphic/poorly differentiated/round cell, 8, including a case of dedifferentiated liposarcoma. Immunohistochemistry studies showed focal positive staining for S100 and CD34 in most ALT/WDL, and desmin and myogenin in 2 cases with evidence of rhabdomyoblastic differentiation. MDM2 positivity was focally seen in 1 case. Follow-up was available in 8 cases. Multiple recurrent tumors were seen in 2 patients, and metastatic disease to the lung was seen in 2 patients. In 4 patients with a follow-up between 2 and 15 years there was no evidence of recurrent or metastatic disease. Patients with ALT/WDL (2/2) were alive with no evidence of disease; 2 of 4 patients with myxoid liposarcoma component experienced tumor recurrence, whereas pleomorphic liposarcoma LPT pursued a less favorable course although only 1 patient died of the condition. Absence of MDM2 reactivity in most cases seems not as meaningful as in fatty tumors of somatic soft parts.

Unmasking of proteinuria in the course of genetic dissection of nonproteinuric diabetic nephropathy.

We previously described the development of nonproteinuric diabetic nephropathy (NPDN) in the Cohen diabetic rat (CDs), a model that simulates Type 2 diabetes in humans. Using linkage analysis in an F2 cross, we currently set out to investigate the mechanisms underlying NPDN. We crossbred between CDs and SBN/y, a nondiabetic rat strain, generated F1 and F2 progenies, fed them diabetogenic diet that elicits diabetes and NPDN in CDs but not in SBN/y, and determined metabolic and renal phenotypes. Over 5 mo, ∼75% of F2 developed a diabetic phenotype. In parallel, a nephropathy developed in F2, with glomerular filtration rate (GFR) declining in ∼25% and, unexpectedly, significant proteinuria appearing in ∼75%. We scanned the F2 genome with microsatellite markers and used linkage analysis to identify quantitative trait loci (QTLs). We detected diabetes-related QTLs on RNO4 and 13. We also detected two QTLs for the decline in GFR on RNO4 and 13 and another QTL for proteinuria on RNO13. The metabolic and renal-related QTLs overlapped. These results suggest that the mechanisms underlying the nephropathy in F2 are related to genes that map to RNO4 and 13, as well as a common genetic background for the development of diabetes and the renal disease. Our findings further indicate that proteinuria is inhibited in parental diabetic CDs, thus accounting for the nonproteinuric phenotype, but "unmasked" in diabetic F2 whose genome has been modified. Identifying the nature of the factor inhibiting proteinuria in diabetic CDs but not in F2 may provide a clue to treatment and prevention of proteinuria in diabetes.

Selected case from the Arkadi M. Rywlin International Pathology Slide Series: Leiomyomatosis peritonealis disseminata: report of 3 cases with extensive review of the literature.

We present the clinicopathologic features of 3 cases of leiomyomatosis peritonealis disseminata (LPD). The patients were 33, 34, and 41 years old at the time of diagnoses. The 3 women had undergone laparoscopic removal of multiple uterine leiomyomas between 1 and 6 years before the diagnoses of LPD. Laparoscopic uterine leiomyomectomies were performed on 3 occasions in patient 1, and once in patients 2 and 3 by the time a diagnosis of LPD was made. In patients 2 and 3, one of the multiple uterine leiomyomas had been qualified as mitotically active. Patients 1 and 2 received hormonal treatment before LPD was diagnosed. Malignancy was clinically and/or pathologically suspected in all the 3 cases. Patients 1 and 2 were managed conservatively. Patient 3 underwent radical hysterectomy with bilateral adnexectomy and omentectomy. Patients 1 and 2 belong to a rare subset of LPD that have fewer tumor nodules larger (5 to 10 cm) than typically seen. Patient 3 was classic in that she exhibited innumerable nodules measuring between a few millimeters and 1.5 cm, intraoperatively mimicking peritoneal carcinomatosis. Histopathologically, patients 1 and 2 were diagnosed as pure LPD, whereas patient 3 was diagnosed as LPD associated with endometriosis (adenomyosis type). Patients 1 and 3 had incipient foci of leiomyomatous changes in the blood vessel walls, at the site of the LPD tumors, supporting the hypothesis that these are de novo lesions arising locally and not migrated or disseminated from the previously excised or concurrent uterine smooth muscle tumors, usually seen in this context. Conceivably, laparoscopic leiomyomectomy with morcellation may play a role in the pathogenesis of this rare condition, at least in hormonally susceptible patients. Alternatively, LPD may derive from metaplastic submesothelial cells, a condition analogous to gliomatosis peritonei.

Characterizing the clinical and sociodemographic profiles of hospitalized adolescents with autism spectrum disorder.

The prevalence of autism spectrum disorder (ASD) is increasing worldwide. Youngsters with ASD demonstrate higher rates of intellectual disabilities (IDs), comorbid psychopathology and psychiatric hospitalizations, compared to children in the general population. This study characterizes the demographics and clinical parameters of adolescent psychiatric inpatients with ASD compared to inpatients without ASD, all hospitalized during the study period. Additionally, within the ASD group, those with ID were compared to those without. The rate of males among participants with ASD was significantly higher than among those without ASD, and the duration of hospitalization was longer. In contrast, the rate of cigarette smoking, major depressive disorder and suicidal thoughts among those with ASD was lower. One-third of those with ASD had moderate to severe ID, about 10% had comorbid epilepsy, and about half of them demonstrated aggressive behavior. Most ASD patients showed significant improvement upon discharge, although the extent of improvement was more prominent among ASD patients with no ID. Our findings, consistent with previous research, indicate that hospitalization is beneficial to youths with ASD, both those with and those without ID. Further studies that include long-term follow-up are needed.

Radical cystectomy with W-shaped orthotopic ileal neobladder constructed with non-absorbable titanium staples-long term follow-up.

PURPOSES: We retrospectively assessed our experience with the W-shaped orthotopic ileal pouch, which was constructed with non-absorbable titanium staples. For these purpose, we discuss the results of bladder capacity, urinary continence and early and long-term postoperative complications. MATERIALS AND METHODS: We included in the study 17 patients who underwent radical cystoprostatectomy followed by construction of an orthotopic W-shaped ileal pouch between October 2000 and November 2009. A 65-70 cm segment of ileum was isolated and prearranged into a W-configuration, leaving two 10 cm intact segments on both sides of the ileal fragment. In our technique we entirely anatomized all adjacent limbs in order to create a sphere-shaped pouch. The ureters were directly anastomized to both intact segments of the ileal division. All our patients underwent pouchscopy 6 months after operation and annually. RESULTS: Mean operative time for neobladder reconstruction and ureteral anastomoses was 87 ± 7.67 minutes. In one patient a leak from the ileo-ileal anastomosis was confirmed on the 3rd day after operation. In 2 cases unilateral stricture of the ureteral-neobladder anastomosis was documented. Staple lines were mostly covered with ileal mucosa after 6 months. The mean functional bladder capacity was 340 ± 27.6 mL and 375 ± 43.4 mL at 6 and 12 months, respectively. First-year daytime and nighttime continence was good and acceptable in 90% and 78% of patients, while it increased to 95% during the 2nd year. CONCLUSIONS: The long term follow-up shows that non-absorbable titanium staples can be safely used for creation of an orthotopic ileal neobladder. However, these data should be further validated in a larger series of patients.

Phenotypic Characterization of Youth Admitted To Acute Psychiatric Inpatient Unit Following Self-Harm Behavior.

OBJECTIVE: Deliberate self-harm (DSH) is a major health concern among adolescents, and is often associated with the need for inpatient psychiatric hospitalization. The aim of this study was to identify clinical and demographic characteristics associated with DSH behavior among adolescents admitted to an acute psychiatric inpatient unit. METHOD: We retrospectively analyzed data from the electronic medical records of consecutive admittances to a single acute adolescent inpatient unit (n = 703, mean age 15.2). We compared inpatients with DSH to inpatients without DSH and further compared within the DSH group based on the presence of suicidal intent. RESULTS: Compared to Non-DSH inpatients (n = 497), youths admitted following DSH (n = 206) were more likely to be female (OR = 2.6, 95%CI 1.7-4), currently in depressive exacerbation (OR = 2.4, 95%CI 1.6-3.6), with concurrent suicidal ideation (OR = 3.9, 95%CI 2.5-5.9), and history of alcohol use (OR = 5.6, 95%CI 3.2-9.5). Within DSH youths, no significant clinical differences were identified between those admitted following a suicide attempt (n = 102) compared to non-suicidal-self-injury (n = 104), who were generally younger. CONCLUSIONS: Findings suggest that early detection and intervention of DSH and depressive crisis is warranted, regardless of the self-harm subtype.HIGHLIGHTSDeliberate self-harm is common among adolescent psychiatric inpatients.Adolescent inpatients with deliberate self-harm are predominantly females with concurrent depression and suicidal ideation.We did not detect significant clinical and demographic differences between self-harmers with or without suicidal intent.

Association between neutrophil to lymphocyte ratio and mood polarity in adolescents admitted to an inpatient psychiatric ward.

Inflammatory processes are associated with mood disorders, but data on pediatric patients are scarce. The aim of this study was to investigate a possible association between elevated neutrophil/lymphocyte ratio (NLR) - a marker of inflammation and mood polarity (manic/depressed) in adolescents, admitted between 2010 and 2015 due to a mood disorder episode and to an adolescent inpatient ward. Electronic medical records of 305 patients (aged 10-19 years, 60.6% males) admitted during the study period due to a mood disorder episode were reviewed. Of these, 63 were diagnosed with manic episodes and 242 with depressive episodes. Multivariate analyses were used to compare NLR between and within the two groups, covarying for age, sex, and antipsychotic use. NLR was significantly higher in the manic episode group compared with the depression one. Moreover, in inpatients with multiple hospitalizations, the NLR was higher during their manic episodes than that during their nonmanic states. These results suggest that, as has been reported in adults with bipolar disorder, inflammatory mechanisms may be involved in adolescents' mood disorders as well, particularly in the manic episodes. Thus, clinicians may consider adding anti-inflammatories as part of the treatment of these patients.

Selected case from the Arkadi M. Rywlin International Pathology Slide Seminar: Sporadic lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a systemic, progressive, and fatal condition affecting almost exclusively women in their reproductive years. LAM most often occurs as a sporadic disease, but also occurs in women with tuberous sclerosis complex (TSC) (syndromic LAM). There are no pathologic differences between sporadic and syndromic LAM. Sporadic LAM is a rare disease with prevalence of approximately 1 to 2 cases per million women in the United States and among populations of white descent, and is even rarer among Asian and African individuals. Syndromic LAM affects 4% to 5% of women with TSC. Sporadic LAM is often found also in association with renal angiomyolipoma, the most common sign of TSC, but LAM associated with angiomyolipoma does not define TSC. Although LAM is not diagnostic for TSC either in isolation or in association with angiomyolipoma, still it is considered by some researchers as an incomplete expression (forme fruste) of TSC. LAM may involve the lungs and the axial lymphatics and lymph nodes of the thorax and retroperitoneum. In sporadic LAM, thoracic, intraabdominal, and cervical lymph nodes can be involved with or without lung involvement. The diagnosis of LAM is often delayed. A case of LAM in a young lady, which was complicated with pleural and peritoneal chylous effusions, is presented. The diagnosis was first made on a retroperitoneal lymph node biopsy. The patient had a prolonged prior history of respiratory problems owing to lung involvement, and eventually died 2 years after diagnosis. Focus on the clinicopathologic diagnosis of TSC is also made.

The association of non-suicidal self-injurious and suicidal behaviors with religiosity in hospitalized Jewish adolescents.

Religiosity may be a potent protective factor against self-injurious and suicidal behaviors. However, no previous study has addressed this relationship in adolescent psychiatric population. This study aimed to examine the association between religiosity and non-suicidal self-injurious (NSSI) and suicidal behaviors, among hospitalized Jewish adolescents. This is a cross-sectional study of 60 hospitalized Jewish adolescents in two mental health centers. They were evaluated for religiosity, NSSI, and suicidal behaviors. The following religiosity measures were found to be protective against NSSI: a higher degree of adherence to religious practices (extrinsic measure) (beta = -0.083, p = .006), a higher level of belief in religious principles (intrinsic measure) (beta = -0.063, p = .008) and a self-reported higher religious affinity (χ2 = 7.64, p = .022). The severity of suicidal ideation inversely correlated with the extrinsic measure (standardized beta = -0.2, t = -2.5, p = .015) and with self-reported degree of religious affinity (analysis of variance, F = 3.5, p = .035). History of transition in religious affinity was associated with worse suicidal ideation (3.77 ± 1.8 vs. 2.26 ± 1.99, t = -3.25, p = .004) and with suicide attempts (OR = 3.89 (95% CI: 1.08 - 14.03), p = .004); however, these relationships were mediated by history of abuse. This study provides first evidence of a protective effect of some religiosity measures on NSSI and suicidal behaviors in hospitalized Jewish adolescents.

Predictors of Suicidal Behaviors during Hospitalization among Adolescents Admitted Due to Suicidal Behaviors: A 10-Year Retrospective Naturalistic Study.

Objectives: Suicidality during hospitalization is a common phenomenon with potential devastating consequences. We attempted to identify risk factors for in-hospital suicidality in a high risk group of adolescent inpatients hospitalized for suicidal behaviors (SB). Methods: The database of a tertiary adolescent psychiatric ward was screened for patients hospitalized consecutively for SB during 2001-2010. Data on documented demographic, clinical, and behavioral risk factors were collected. Suicidal events during hospitalization were classified according to the Columbia Classification Algorithm of Suicide Assessment. Results: The sample included 122 inpatients (53% female) aged 10-19 (Mean=15.77, Standard Deviation=2.89) years admitted for SB. Thirty-seven youth (30%) exhibited SB during the hospitalization period (the "suicidal group"), ten of which attempted suicide while hospitalized. There were no significant differences in demographic and clinical parameters between the suicidal and the non-suicidal groups. Younger age, history of drug use and a history of non-suicidal self-injury (NSSI) were independent predictors of a SA during hospitalization. A previous SA added significant risk to SA during hospitalization only in the group that had a history of NSSI. Conclusions: A high risk of SB exists among adolescents hospitalized for suicidality. The risk assessment for SA during hospitalization should include age, history of drug use and previous SA combined with a history of NSSI. Future studies should expand the efforts to identify potential risk factors of SB during hospitalization in this unique high-risk group.

A history of prolonged childhood sexual abuse is associated with more severe clinical presentation of borderline personality disorder in adolescent female inpatients - A naturalistic study.

BACKGROUND: Borderline personality disorder (BPD) is associated with high rates of suicidal and self-injurious behaviors and a substantial proportion of BPD patients have a history of trauma, particularly childhood sexual abuse (CSA). OBJECTIVE: To compare the clinical presentation severity in female adolescent inpatients with BPD with and without history of prolonged CSA. PARTICIPANTS AND SETTING: Female adolescent BPD patients admitted to a psychiatric inpatient unit. METHODS: A retrospective analysis of records of the inpatients, divided into two groups: with (n = 38) and without (n = 40) a history of prolonged CSA. Prolonged CSA was defined as sexual abuse continuing for at least 3 months. Demographic and clinical data, including number and duration of psychiatric hospitalizations until the age 19, non-suicidal self-injury (NSSI), suicide attempts, cigarette smoking, alcohol and drug use, and sexual impulsivity were compared between the two groups. RESULTS: The BPD + prolonged CSA group had a larger duration of the first psychiatric hospitalization, number of hospitalizations and cumulative length of hospitalizations compared with the control group. Furthermore, the BPD + prolonged CSA group had a higher number of suicidal attempts, and higher rates of severe NSSI events, cigarette smoking, alcohol use, and sexual impulsivity. CONCLUSIONS: This study demonstrated for the first time that adolescent female BPD inpatients with a history of prolonged CSA, manifest more severe clinical presentation compared to those without prolonged CSA. Hence, it appears essential to encourage therapists to inquire about history of CSA and refer adolescent female BPD inpatients with prolonged CSA to appropriate intensive therapy.

Tuberous sclerosis complex with polycystic kidney disease of the adult type: the TSC2/ADPKD1 contiguous gene syndrome.

Although different diseases, tuberous sclerosis complex and autosomal dominant polycystic kidney disease have been seen in association, the molecular basis of this being the proximity of tuberous sclerosis complex 2 and polycystic kidney disease 1 genes on the same chromosome (16p13.3). Therefore, the classic autosomal dominant polycystic kidney disease renal phenotype may occur in the context of tuberous sclerosis complex disease as a result of large deletions involving both the polycystic kidney disease 1 and tuberous sclerosis complex 2 genes. This is known as the tuberous sclerosis complex 2/autosomal dominant polycystic kidney disease 1 contiguous gene syndrome. The criteria for this condition are fulfilled when renal lesions typical for classic autosomal dominant polycystic kidney disease phenotype are associated with tuberous sclerosis complex phenotype. We present a new case of the sporadic form of this genetic disorder. The diagnosis of tuberous sclerosis complex in this patient was established on the presence of major and minor features, and the diagnosis of ADPKD was based on the presence of numerous large roundish renal cysts lined by a nondescript tubular epithelium. Sporadic cases of autosomal dominant polycystic kidney disease and tuberous sclerosis complex do occur. Molecular analysis was not performed because the patient's parents refused permission.

Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene.

Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as "hemangioblastoma-only VHLD", 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas, and LOH in 4 (two as a double hit), all non-renal extraneuraxial hemangioblastomas. Methylation analysis failed to disclose promoter methylation in any case. In conclusion, we report eight new cases from the wide category of extraneuraxial hemangioblastomas (4 paraneuraxial, and 4 renal), one of which was von Hippel-Lindau disease-associated and 7 sporadic. VHL gene alterations were found not only in the von Hippel-Lindau disease-associated tumor, but - for the first time - also in 3 sporadic ones, two of which with novel mutations.

Differences in demographic and clinical characteristics between cannabis users and non-drug users: A retrospective study of patients at first hospitalization due to psychotic symptoms.

This retrospective, chart review, cohort study compared demographic and clinical characteristics of cannabis -users and non-drug users at first admission due to psychotic symptoms at Geha Mental Health Center, Israel, between August 2002 and December 2013. We assessed the role of current cannabis use as a risk for re-hospitalization during this period as well as the stability of psychotic diagnoses at re-hospitalization. A total of 318 patients were included in the study, of which 106 (33.3%) were cannabis -users. The cannabis-user group had a shorter duration of hospitalization than the non-drug user group but without a significant difference in 5-year re-hospitalization rates. The latter had a higher rate of severe mental illness (SMI) diagnoses at first hospitalization (53.3% vs. 20.3%, respectively), but the difference disappeared at the second hospitalization. The two groups demonstrated a 79-80% rate of conversion from a non-SMI to an SMI diagnosis between the admissions. The results indicate the instability of non-SMI diagnoses at first hospitalization due to psychotic symptoms, regardless of concurrent cannabis use. The high conversion rate from non-SMI to SMI in current cannabis-users may be due to under-diagnosis of SMI at first admission or an effect of cannabis on the development of SMI.

Elevated neutrophil to lymphocyte ratio in non-affective psychotic adolescent inpatients: Evidence for early association between inflammation and psychosis.

Accumulating data suggest an association between inflammation and schizophrenia and related psychosis. While several studies have established this immune-psychosis association in adult schizophrenia patients, there is very limited data associating inflammation with acute psychosis in children and adolescents. The ratio between neutrophils and lymphocyte, computed from routine blood counts, has been shown to correlate with traditional markers of inflammation, and is therefore considered a proxy-marker for inflammation. Here we report elevated neutrophil to lymphocyte ratio and total leukocyte count in psychotic adolescent inpatients (n = 81, mean age 14.7 years, 52% males) compared to non-psychotic adolescent inpatient (n = 285, mean age 15.9 years, 58% males), in a population of adolescent inpatients with no affective symptomatology. The elevated neutrophil to lymphocyte ratio remained significant after controlling for confounders such as age, BMI, smoking and antipsychotic medication. In a subset of psychotic adolescent inpatients (n = 20, mean duration between blood test 157 days), we found significant decrease in neutrophil to lymphocyte ratio at clinical remission compared with the acute psychotic state. The results suggest that psychosis is associated with peripheral markers of inflammation early in the course of psychiatric pathology, and that inflammation may represent a state that accompanies psychosis and decreases during clinical remission.